The uncontrolled growth of breast cancer cells in vital organs is attributable to nearly all the ~40,000 deaths that happen each year in the United States. The long-term goal of this project is to identify new therapeutic strategies to overcome chemotherapy resistance in triple-negative breast cancers (TNBC). The objective of this proposal is to identify biological pathways that can be targeted in addition to the epidermal growth factor receptor (EGFR) to promote apoptosis of disseminated cancer cells. The central hypothesis is that EGFR inhibition leads to activation of cellular stress responses that can be targeted with pro-apoptotic agents. The goal at the completion of this project is for the results to immediately translate to the clinical setting and provide options for current patients with metastatic disease. The proposed work will also develop a unique dataset that can be used for further research towards identifying and developing targeted inhibitors that bypass carboplatin-resistance. The central hypothesis will be tested by pursuing two specific aims: 1) Delineate targetable pathways that are synergistic with Afatinib for cytotoxicity of carboplatin-resistant TNBCs; 2) Determine the efficacy of Afatinib- synergsitic combinations in multiple diverse in vivo models of TNBC. These aims will be pursued using an innovative set of patient-derived xenograft models (PDX) which consist of isogenic pairs that are carboplatin- sensitive or those that have been generated to be carboplatin-resistant. This research proposal is significant because it will identify new therapeutic targets that can be used to treat patients with advanced disease, and then compare the effectiveness of various targeted combinations on surgically unresectable metastases. The expected outcome of these efforts is that we will identify subsets of TNBC PDXs that will favorably respond to Afatinib-based combination therapies, and subsequently that we will identify genomic and/ or proteomic predictors of anti-EGFR response that will make a positive impact on disease management by identifying patients that may benefit from this treatment approach.